Emulsions (Liquid-Liquid System) PDF

Emulsions (Liquid-Liquid system) Contents 1. Introduction 2. Applications 3. Theory of emulsification 4. Emulsion types 5. Formulation components 6. Emulsion formation 7. Equipments used 8. Production aspects 9. Stability  Definition ▪ An emulsion is a two phase system consisting of two immiscibl...

Emulsions (Liquid-Liquid system) Contents 1. Introduction 2. Applications 3. Theory of emulsification 4. Emulsion types 5. Formulation components 6. Emulsion formation 7. Equipments used 8. Production aspects 9. Stability  Definition ▪ An emulsion is a two phase system consisting of two immiscible liquids, one of which is dispersed throughout the other in the form of fine droplets which is generally stabilized by an emulsifying agent. ▪ A heterogeneous system consisting of at least one immiscible liquid dispersed in another in the form of droplets whose diameter generally exceeds 0.1 um. ▪ An emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid phases one of which is dispersed as globules in the other liquid phase stabilized by a third substance called emulsifying agent. ▪ An intimate mixture of two immiscible liquids that exhibits an acceptable shelf life near room temperature. Introduction Usually only one phase persists in droplet form for a very prolonged period of time. This phase is called internal phase or disperse phase or discontinuous phase. The internal phase is surrounded by external continuous phase. The internal phase can occupy no more than 74 % of the total volume of an emulsion. It can exceed 74 % if the spherical particles are not mono disperse. An emulsifier is added to increase the lifetime of the droplets in two immiscible liquids. It can be defined as a stabilizer of the droplet form (globules) of the internal phase. On the basis of their structure, emulsifiers (wetting agents, surfactants) may be described as molecules comprising of both hydrophilic (oleophobic) and hydrophobic (oleophilic) portions. These are commonly called amphiphilic (water and oil loving). Most common emulsions include water as one of the phase and an oil or lipid as the other. Introduction If the oil droplets are dispersed in a continuous phase, the emulsion is termed oil in water (o/w). If the oil is the continuous phase, the emulsion is of water in oil type (w/o). o/w emulsions occasionally change into w/o emulsion and vice versa. The change of emulsion type is called inversion. Multiple emulsions include : 1. Oil in water in oil emulsion (o/w/o) 2. Water in oil in water emulsion (w/o/w) Such emulsions can also invert and during inversion they usually form simple emulsions. A w/o/ w emulsion normally yields an o/w emulsion. Types of Emulsions Micro/Nano emulsions Multiple thermodynamically emulsions Simple stable, emulsions Oil-in-water-in-oil optically (Macro (O/W/O) transparent , emulsions) Water-in-oil-in- mixtures of a Oil-in-water (O/W) water biphasic oil Water-in-oil (W/O) (W/O/W) –water system stabilized with - diameter surfactants greater than Size range 0.1 μm 0.01-0.1 um. Introduction The particle size of the disperse phase determines the appearance of an emulsion. The radius of droplets in an opaque, usually white, emulsions ranges from 0.25 to 10 um. Particles less than 1/4th the wavelength of visible light do not refract light and therefore appear transparent to the eye. Such dispersions yield micro emulsions or micellar emulsions. In microemulsions, the disperse phase have a radius in the range of 10 to 75 nm. Transparent emulsions, solubilized oils, micellar emulsions and microemulsions are all same as they all appear clear. The production of a transparent dispersion of an oil by micellization does not result in the formation of droplets, but in the inclusion of lipids into micelles. Applications Emulsions have a variety of cosmetic and pharmaceutical applications. The latter can be classified by the route of administration ie, topical, oral, or parenteral. 1. Emulsions have wide patient acceptance in oral dosage forms. Medicinal agents having objectionable taste or texture can be made more palatable when formulated into emulsions. Mineral oil based laxatives, oil soluble vitamins and high fat nutritive preparations are commonly administered as o/w emulsions. 2. High efficacy (BA or absorption):- normally unabsorbable macromolecules eg, heparin and insulin are absorbed when incorporated into emulsions. 3. Patient acceptance in topical emulsions. Emulsions are easily washed off and have certain degree of elegance. The formulator can control the viscosity, appearance, and degree of greasiness of cosmetics or dermatologic emulsions. 4. o/w emulsions are most useful as water washable drug bases and for general cosmetic purposes. w/o emulsions are widely used for the treatment of dry skin and emollient applications. Penetration is desirable and refers to the disappearance of the product or of oiliness from the skin during injuction. This process is facilitated if the emulsion is thixotropic. Applications 5. Emulsions have been used for the intravenous administration of lipid nutrients. Such o/w emulsions require rigorous control of emulsifying agent or particle size. 6. Radiopaque emulsions have been used as diagnostic agents in X ray examination 7. W/o emulsions have been used for intramuscular depot injection. The presence of emulsifier may help to lower the tendency of drug to crystallize and cause thrombophlebitis. 8. Emulsification of perflourinated hydrocarbons is required to make them useful as oxygen carriers in blood replacements. 9. Most lipids and solvents for lipids that are intended for application to or into the human body are relatively costly. As a result, dilution with a safe and inexpensive diluent, such as water is highly desirable from an economic point of view.  Emulsion type To understand the factors whether an o/w or w/o emulsion will be produced, critical features should be considered. 1) droplet formation 2) formation of an interfacial barrier ❑ The phase volume ratio ie, the relative amount of oil and water, determines the relative number of droplets form and hence the probability of collision. The greater the number of droplets, the greater is the chance for collision. Thus normally the phase present in greater amount becomes the external phase. ❑ If the amphiphile is water soluble (potassium soap or polyoxyethylene oxide units), it will usually favour o/w emulsification. If the surfactant is primarily soluble in lipid portion (Calcium soap, polyoxyethylene alkyl ether with less than 5 ethylene oxide units), it may yield w/o emulsions.  Emulsion type ❑ The polar portions of emulsifier molecules are better barriers to coalescence than their hydrocarbon counterparts. It is possible to make o/w emulsions with relatively high internal phase volumes. W/o emulsions (barrier is of hydrocarbon nature) are limited and can invert easily if the amount of water is significant. At 20% and 30% water, w/o emulsion form only if the water is added to the oil with mixing. The addition of both phases together, followed by mixing, favors o/w emulsions at all concentrations above 10 % water. ❑ Type of emulsion formed is influenced by the viscosity of each phase. An increase in the viscosity of a phase aids in making that phase the external phase. One can expect a predominantly water soluble emulsifier to form o/w emulsions, whereas the reverse is true of primarily oil soluble surfactants --------Bancroft’s rule. Determination of type of emulsion Micro emulsions Micro emulsions may be defined as dispersions of insoluble liquids in a second liquid that appear clear and homogeneous to the naked eye. Also called solubilized systems because on macroscopic basis they seem to be true solutions. Careful examination has shown that clear emulsions can exist in several differentiable forms. If the small amount of oil is added to an aqueous solution of a surfactant in the micellar state, the oil may preferentially dissolve in the interior of the micelle because of its hydrophobic character. This type of micellar micro emulsions has also been called o/w micellar solution. w/o solubilization -- by a non ionic surfactant has been attributed to the existence of swollen micelles. Also called reverse micellar solution, water molecules are found in the polar central portion of a surfactant micelle, the non polar portion of which is in contact with the continuous lipid phase. Another type of microemulsion (mostly w/o ) is formed by ionic surfactants. (sodium stearate) in the presence of co-surfactant (pentanol or dioxyethylene dodecyl ether) with hydrocarbons and water. Formulation components Formulation components used in emulsions include:- 1. Lipid phase 2. Emulsifying agents (surfactants, HLB concept, required HLB, PIT, determination of surfactant amount, HLB system shortcomings) 3. Auxiliary emulsifiers (hydrophilic colloids, finely divided solids) 4. Viscosity modifiers 5. Antimicrobial preservatives 6. Antioxidants Additives For Formulation Of Emulsion Anti- oxidants Emulsifying agent Antimicrobial Preservative Auxiliary Emulsifiers I. Lipid phase The material of the oil portion and its amount is determined by the use of the product. For pharmaceutical and cosmetic products, the oil phase may include a wide variety of lipids of natural or synthetic origin. The consistency of these lipids may range from mobile liquids to fairly hard solids. The drug’s absorption in the git or the skin depends on its solubility in the oil phase. The release of a medicinal agent from a dosage form is a function of the solubilities of the agent in the base and in the body membrane. The drug must not be so soluble in the base that it prevents penetration or transfer. Selection of a lipid component for topical preparation depends on its feel. Emulsions normally leave a residue of oily components on skin after the water has evaporated. Phase ratio: the ratio of the internal phase to the external phase is normally determined by the solubility of the active ingredient, which must be present at a pharmacologically effective level. If this is not the primary consideration, the phase ratio is normally determined by the desired consistency. II. Emulsifying agent These may be differentiated into 3 broad classes of emulsifying agents: 1. The surfactants 2. The hydrophilic colloids 3. Finely divided solids A particular class of emulsifier is selected on the basis of required “shelf life” stability, the type of emulsion desired, and emulsifier cost. Hydrophillic colloids and finely divided solids are commonly used as an auxillary emulsifiers.  a) Surface active agents or surfactants Substances having both hydrophilic and hydrophobic regions in their molecular structures are called surface active agents or surfactants. These are soluble in both oil and water as well. Upon addition of the surfactant into the dispersed system, the hydrophilic (polar) and hydrophobic (non polar) groups orient themselves in a mono molecular layer facing the polar (water) and non polar (oils) solvents respectively. The interfacial tension must be lowered for the interface to expand and hence the dispersed system will be emulsified. Surfactants are classified into 4 main categories depending upon the nature of the charge by the hydrophilic part:- 1. Anionic 2. Cationic 3. Non ionic 4. Ampholytic surfactants a) Surface active agents or surfactants 1. Anionic surfactants These are negatively charged Sodium lauryl sulfate, is highly soluble in water and commonly used to form o/w emulsions. Alkali hydroxide reacts with fatty acids can produce alkali metal soaps eg, sodium oleate. Alkali earth metal soaps (calcium oleate) produces stable w/o emulsions because of their low water solubility. Triethanolamine stearate produces stable o/w emulsion. 2. Cationic surfactants These are positively charged in aqueous solution Eg, quarternary ammonium and pyridinium These are expensive Because of their bactericidal action, they are widely used as preservatives, sterilizing contaminated surfaces and emulsions 3. Non ionic surfactants These consists of OH or (C2H4O)n OH as hydrophilic group These exhibit a variety of hydrophile-lipophile balance (HLB). These are useful in oral and parenteral formulations because of their low irritation and toxicity. They are neutral in nature and are much less sensitive to pH of the medium and the presence of electrolytes. Sorbitan esters (spans) are the products of the esterification of a sorbitan with a fatty acid. They are not soluble in water and used for w/o emulsions. Polysorbates (tweens) are water soluble, hence used as an emulsifying agent for o/w emulsions. Fatty alcohol polyethylene ethers and fatty acid polyoxyethylene esters are water soluble and used to give o/w emulsions in conjunction with auxiliary emulsifiers. 4. Ampholytic surfactants These possess both cationic and anionic groups in the same molecule and are dependent on the pH of the medium. Lecithin used for parenteral emulsions  Hydrophilic-Lipophilic Balance (HLB) Concept Griffin in 1947 developed system of HLB of surfactants. The HLB value of an emulsifier can be determined experimentally or can be computed as long as the structural formula of the surfactant is known. ▪ The HLB values of the surfactants based on polyhydric alcohol fatty acid esters may be estimated by:- HLB = 20 (1- S/A) S= saponification number of the ester A=acid number of the fatty acid  Hydrophilic-Lipophilic Balance (HLB) Concept ▪ If the saponification number cannot be obtained (eg, beeswax, lanolin derivatives), their HLB values may be calculated by:- HLB = (E+P)/5 E= weight percent of oxyethylene chains the surfactant P= weight percent of polyhydric alcohol group (eg, glycerol, sorbitol) ▪ If the hydrophilic region is polyoxyethylene, the HLB vaue is calculated:- HLB = E/5 Hydrophilic-Lipophilic Balance (HLB) Concept Davies proposed a method of calculation of HLB by algebraically adding the value assigned to a particular atomic grouping within the molecule of the emulsifier. ∑ ∑ HLB of surfactant = (hydrophilic groups) - (hydrophobic groups) + 7 The appropriate combination of surfactants should be chosen to form the most stable emulsion. The HLB value of the mixture of surfactant A (HLBA) and (HLBB) is calculated by: HLBmixtures = fAX HLBA + (1-fA) HLB B fA = weight fraction of surfactant A in the mixture Hydrophilic-Lipophilic Balance (HLB) Concept The molecules that are oil soluble and oil-dispersible have low HLB values, while those are water soluble have high HLB values. The HLB required for emulsifying particular oil in water can be determined by trial and error. Phase inversion temperature (PIT) Important influence of heat on emulsion is phase inversion The temperature at which phase inversion occurs is called phase inversion temperature (PIT) Maximum particle size reduction occurs at or near PIT. At this temperature, surfactants that are normally water soluble may actually become soluble in the oil phase. As the emulsion cool, emulsifiers migrate eg by changing their location from the internal to external phase. This type of inversion occurs during preparation since they are generally prepared at high temp and then lowered to cool temperature. Emulsions prepared by this method is considered quite stable and contain finely dispersed internal phase. Determination of surfactant amount This can be achieved by determining the amount of water that can be solubilized in a given oil plus surfactant mixture under carefully controlled temperature and stirring conditions. The most stable o/w emulsion with the finest particle size results at that surfactant/oil ratio that can tolerate the largest quantity of water and still remain clear. HLB shortcomings There is no assurance that a stable emulsion prepared from one chemical class of emulsifiers at a particular HLB can be duplicated by another class of emulsifiers exhibiting the same HLB. HLB required for a particular emulsion to some extent depends on the phase ratio and the salt content. III. Auxiliary (secondary) Emulsifiers Auxiliary (Secondary) emulsifying agents include those compounds that are normally incapable themselves of forming stable emulsion. Their main value lies in their ability to function as thickening agents and thereby help stabilize the emulsion. They increase the viscosity of the external phase and restrict the collision of droplets. Some may prevent coalescence by reducing van der waal’s forces between particles or by providing a physical barrier between droplets. Example:- Proteins Clays Methylcellulose Carboxymethyl cellulose Auxiliary emulsifiers 1. Hydrophilic colloids Water sensitive (swellable or soluble) polymers are used as primary emulsifiers, but their major use is as auxiliary emulsifiers and thickening agents. Natural and synthetic clays of smectite or amphibole groups are used for building viscosity of emulsions or for suspending solids. Bentonites, derived from montmorillonite, is a typical smectite clay and are most commonly used. These swell in the presence of water but raise the viscosity of aqueous media only at pH 6 or higher. Clays derived from amphibole group eg, attapulgite, thicken not by swelling but because of particle anisotropy. Naturally occurring gums and synthetic hydrophilic polymers are useful as emulsifiers and as emulsion stabilizers. Most natural hydrocolloids are polysaccharides. These show incompatibility depending upon pH or on second hydrophilic polymer. Auxiliary emulsifiers 1. Hydrophilic colloids Useful hydrocolloids are ethers derived from cellulose. Synthetic group of polymers include carboxy vinyl polymer. Water sensitive hydrocolloids favour o/w emulsions because they form excellent hydrophilic barriers. Proteins are effective as primary emulsifiers and as auxiliary emulsifiers and particularly useful in oral dosage forms. Auxiliary emulsifiers 2. Finely divided solids Finely divided solids have been shown to be good emulsifiers, especially in combination with surfactants and/or macromolecules that increase viscosity. These include polar inorganic solids (heavy meta hydroxides, non swelling clays, pigments) and non polar solids (carbon or glyceryl-tristearate). Polar solids tend to be wetted by water to a greater extent than by the oil phase, whereas the reverse is true for non polar solids. In the absence of surfactants, w/o emulsions are favored by the presence of non polar solids and o/w emulsions are favored by the presence of polar solids. In the presence of wetting agents, their behavior is controlled by young’s equation. Eg, barium sulphate in the presence of sodium laurate (pH 12) favors o/w emulsion, whereas barium sulphate coated with sodium dodecyl suphate favors w/o emulsions. IV. Viscosity modifiers A consistency that provides the desired stability and appropriate flow characteristics must be attained. Viscosity can be altered by manipulating the composition of the lipid phase by variations in the phase ratio and the surfactants and by the addition of gums. The use of gums, clays and synthetic polymers in the continuous phase is a powerful tool for enhancing the emulsion’s stability. According to stoke’s law, an increase in viscosity generally minimizes creaming or sedimentation. Since emulsions should show flow or spread, thixotropy in emulsions is required. In a freshly prepared emulsion, building of viscosity requires time. Therefore, a newly formulated emulsion is allowed to rest 24 to 48hrs before determining its rheologic properties.  IV. Viscosity modifiers The viscosity responds to changes in composition in accordance with following generalizations:- 1. There is a linear relationship between emulsion viscosity and the viscosity of the continuous phase. For o/w emulsions, the use of gums and clays is used to increase viscosity while for w/o emulsions, the addition of polyvalent metal soaps or high melting waxes and resins in oil phase increases the viscosity. 2. To control the emulsion viscosity, 3 interacting effects must be balanced :- The viscosity of o/w and w/o emulsions can be increased by reducing the particle size of the dispersed phase Emulsion stability is improved by reducing particle size Flocculation or clumping, can tend to stabilize the emulsion and also increase its viscosity. 3. The viscosity of emulsion increases upon aging.  IV. Antimicrobial preservatives Microbial contamination may occur during the development or production of an emulsion or during its use. It can arise from the use of impure raw materials or from poor sanitation during preparation. Contamination may be the result of invasion by an opportunistic microorganism. Or the consumer may inoculate it during use. Prevention of contamination is recommended. Most important precaution is the use of uncontaminated raw materials including water. Secondly meticulous housekeeping and careful cleaning of equipments (with live steam) is required. Once an uncontaminated product is prepared, a mild antimicrobial agent is enough. The preservative system must be effective against invasion by a variety of pathogenic organisms and be adequate to protect the product during use. The preservatives must meet the general criteria of low toxicity, stability to heat and storage, chemical compatibility, reasonable cost, acceptable taste, color and odor. Efficacy against variety of organisms is required. IV. Antimicrobial preservatives The concentration of preservative required depends on its ability to interact with microorganisms. Microorganisms can reside in water or lipid or both, the preservative regardless of its water oil partition coefficient, should be available at an effective level in both phases. It is customary to include a preservative that is soluble in the water and one which is soluble in the oil phase. Eg, esters of p-hydroxyl benzoic acid. The methyl ester is water soluble whereas the propyl and higher esters have no water solubility. Complex problems may arise when:- 1) The preservative may interact with the emulsion ingredients and get inactivated. Eg, alkyl hydroxybenzoates react with emulsion ingredients. The bound preservatives donot exert any antimicrobial effect. Phenolic preservatives are susceptible to interaction with compounds containing polyoxyethylene groups. An amount equal to complexed material is to be added in such case. Or the addition of various alcohols seems to activate p-hydroxybenzoate esters in the presence of non ionics. IV. Antimicrobial preservatives 2) The pH exerts a major influence on the ability of acidic or phenolic preservatives to interfere with microbial growth. These agents are inactivated by converting them into anions. 3) Other factors include phase ratio 4) degree of aeration during preparation 5) the presence of flavors and perfumes some of which have antimicrobial properties. Combination of preservatives are often used, since they have shown to increase the effectiveness of preservation action either by enhancement of the spectrum activity or by some synergistic behavior. V. Antioxidant Many organic compounds are subjected to autoxidation upon exposure to air eg, emulsified lipids. Many drugs incorporated into emulsions are subjected to autoxidation. Upon autoxidation, unsaturated oils, eg vegetable oils give rancidity with unpleasant odor, appearance, and taste. While mineral oil, and related saturated hydrocarbons are subjected to oxidative degradation only under rare circumstances. Autoxidation can be inhibited by the absence of oxygen, by a free radical chain breaker or by reducing agent. The choice of a particular antioxidant depends on its safety, acceptability for a particular use, and its efficacy. These are commonly used at concentrations ranging from 0.001 to 0.1% (w/v). Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), L tocopherol, and the alkyl gallates are particularly popular in pharmaceuticals and cosmetics. BHT and BHA have pronounced odour and should be used at low concentrations. Alkyl gallates have bitter taste, L tocopherol is well suited for edible or oral preparations, such as those containing vitamin A. V. Antioxidant Almost all antioxidants are subjected to discoloration in the presence of light, trace metals and alkaline solutions. Combinations of 2 or more antioxidants have been shown to produce synergistic effects. Eg, alkyl gallates, BHT and BHA are much more effective in the presence of citric, tartaric or phosphoric acid. Emulsion formation Many of the methods include:- 1. Dispersion method 2. Condensation method 3. Phase inversion method 4. Low energy emulsification 1. Dispersion method Emulsion formation by the commonly employed dispersion method requires a process for breaking up the internal phase into droplets and for stabilizing them into the external phase. Usually, the break up of the internal phase is fairly rapid, the stabilizing step and the rate of coalescence are time and temperature dependent. Application of energy in the form of heat, mechanical agitation, ultrasonic vibration or electricity is required to reduce the internal phase into small droplets. The amount of work depends on the length of time. 2. Condensation method An emulsion can be prepared by passing the vapour of a liquid into an external phase that contains suitable emulsifying agents. Disadvantage:- It is a relatively slow method, limited to the preparation of dilute emulsions of materials having a relatively low vapor pressure. Emulsification is affected by changes in temperature in number of ways. These can either favor emulsification or coalescence. An increase in temperature decreases the interfacial tension as well as viscosity. Thus emulsification is favoured by an increase in temperature. At the same time an increase in temperature raises the kinetic energy of droplets and thereby facilitates their coalescence. This kind of instability in normally observed when emulsions are stored at elevated temperatures for long periods of time. Changes in temperature alter the distribution coefficients of the emulsifier between the two phases and cause emulsifier migration. Since the changes in surface tension and viscosity occur simultaneously, temperature cannot be correlated directly with either emulsion formation or stability. 3. Phase inversion method The temperature at which inversion occurs depends on emulsifier concentration and is called phase inversion temperature (PIT). The PIT is considered to be the temperature at which the hydrophilic and lipophilic properties of the emulsifier are in balance and is therefore also called the HLB temperature. This type of inversion can occur during the formation of emulsions, since they are generally prepared at high temperatures and are then allowed to cool to room temperature. Emulsions formed by phase inversion technique are generally considered quite stable and contain finely dispersed internal phase. 3. Phase inversion method Shinoda described the process of phase inversion. An o/w emulsion stabilized by a non ionic polyoxyethylene derived surfactant contains oil swollen micelles of the surfactant as well as emulsified oil. When the temperature is raised, the water solubility of the surfactant decreases, the micelles are broken, and the size of emulsified oil droplets begin to increase. A continued rise of temperature causes separation into an oil phase, surfactant and water. It is near this temperature that now water insoluble surfactant beings to form a w/o emulsion containing both water swollen micelles and emulsified water droplets in a continuous oil phase. 4. Low energy emulsification The principle of low energy emulsification has been formalized by Lin. In low energy emulsification, all of the internal phase but only a portion of the external phase, is heated. After emulsification of the heated portions, the remainder of the external phase is added to the emulsion concentrate or the preformed concentrate is blended into the continuous phase. The temperature for the preparation of emulsion concentrate is critical. In those emulsions in which a PIT exists, the emulsion concentrate is preferably prepared above the PIT, which results in emulsions having extremely small droplet size. By careful control of the variables (emulsification temperature, mixing intensity, amount of external phase employed) , it is reportedly possible to produce emulsions with smaller and more uniform particle size than those resulting from the conventional process. Mechanical equipment for emulsification Almost all methods used for breaking up the internal phase into droplets depend on brute force and require some sort of agitation. When a liquid jet of one liquid is introduced under pressure into a second liquid, the cylindric jet is broken up into droplets. The factors that enter into the breakup of a liquid jet include the diameter of the nozzle, the speed with which the liquid is injected, the density and viscosity of the injected liquid and the interracial tension between the two liquids. A similar breakup into droplets occur when a liquid is allowed to flow into a second liquid that is agitated vigorously. Once the initial breakup into droplets has occurred, the droplets continue to be subject to additional forces due to turbulence, which causes deformation of the droplet and further breakdown into smaller droplets. Mechanical equipment for emulsification Various types of equipments required for droplet breakup and emulsification can be divided into 4 broad categories:- 1. Mechanical stirrers 2. Homogenizers 3. Ultrasonifiers 4. Colloid mill Mechanical equipment for Emulsification During the formulation of an emulsion, the requirements and problems associated with scale up to production size must be considered. The most important factor involved in the preparation of an emulsion is the degree of shear and turbulence required to produce a given dispersion of liquid droplets. The amount of agitation required depends on the total volume of the liquid to be mixed, the viscosity of the system, and the interfacial tension at the oil water interface. The later two factors are determined by the emulsion type, the phase ratio and the type and concentration of emulsifier. Multiple emulsions of the w/o/w type are normally prepared by first forming a w/o emulsion with the aid of a low HLB emulsifier. This w/o emulsion is then slowly incorporated into an aqueous phase that contains an emulsifier of a significantly higher HLB ie, approximately 12 to 14. 1. Mechanical stirrers An emulsion may be stirred by means of various impellers mounted on shafts, which are placed directly into the system to be emulsified. If the viscosity of the emulsion is low, simple top entering propeller mixers are adequate. If the preparation has moderate viscosity or if more vigorous agitation is required, turbine type mixers are employed. Other mixers provided with paddle blades, counter rotating blades or planetary blades are available for special requirements. The degree of agitation is controlled by the speed of impeller rotation. The pattern of liquid flow and efficiency of mixing are controlled by the type of impeller, its position, presence of baffles and the general shape of container. The use of stirrers is often limited when vigorous agitation of viscous systems is required or when extremely fine droplets are needed or when foaming at high shear rates must be avoided.  2. Homogenizers In a homogenizer, the dispersion of two liquids is achieved by forcing their mixture through a small inlet orifice at high pressures. Principle:- when large globules of a coarse emulsion is passed under the pressure through a narrow orifice, they are broken into small globules of high degree of uniformity and stability. Construction:- A homogenizer generally consists of: o A pump-- which raises the pressure of the dispersion between 500 -5000 psi. o An orifice-- through which the fluid impinges upon the homogenizing valve held in place of the valve seat by a strong spring. This valve set up at 90° to the flow of liquid. Working:- As the pressure builds up, the spring is compressed and some of dispersion escapes between the valve and valve seat. At this point, the energy that has been stored in liquid as a pressure is released and subjects the product to intense turbulence hydraulic shear. 2. Homogenizers 2. Homogenizers Homogenizers of varying designs are useful for handling either liquids or pastes, since the rate of throughput is little affected by viscosity. Disadvantage:- Homogenization raises the temperature of the emulsion, and subsequent cooling may be required. Use:- The use of homogenizer is warranted whenever a reasonably monodisperse emulsion of low particle size (1 nm) is required.  3. Ultrasonifiers The production of emulsions by the use of ultrasonic vibrations is also possible. They are useful for the preparation of moderate viscosity and extremely low particle size emulsions. These devices have limited output and are relatively expensive. Commercial equipment is based on the principle of Pohlmn liquid whistle. The dispersion is forced through an orifice at modest pressure and is allowed to impinge on a blade. The pressure range is from 150-350 psi. This pressure causes blade to vibrate rapidly to produce an ultrasonic note. When the system reaches a steady state, a gravitational field is generated at the leading edge of the blade. 4. Colloid mills Homogenizers and ultrasonic equipments depend on sudden changes in pressure. By contrast, colloid mils operate on the principle of high shear, which is normally generated between rotor and stator of the mill. Principle:- the passage of mixed phases of emulsion formula between a high speed rotor and stator. The clearance between rotor and stator is subjected to tremendous shearing production which affects fine dispersions. Advantages:- Used to prepare pharmaceutical suspension and emulsion with particle size less than 1 micron. These mills are used for communition of solids and for the dispersion of suspensions containing poorly wetted solids but also for preparation of relatively viscous emulsions. Spontaneous emulsification Spontaneous emulsification occurs when an emulsion is formed without the application of any external agitation. Emulsifiable concentrates and micro emulsions are typical examples. Production aspects It is possible to design combinations of equipment that permit continuous manufacturing of emulsions. The selection of equipment for production of emulsions is based in part on the production capacity and the power requirements for various types of apparatus. 1. Foaming during agitation:- During the agitation or transfer of an emulsion, foam may be formed. It is because the water soluble surfactant required for emulsification generally also reduces the surface tension at air- water interface. In addition mechanical stirring, especially during cooling, can be regulated to cause the air to rise to the top. To minimize foaming, emulsification may be carried out in closed systems or under vaccum. It is sometimes necessary to add foam depressants (antifoams), but their use should be avoided because they represent a chemical source of incompatibility. Sometimes the use of ethyl alcohol accelerates the coalescence of foam on the surface of emulsion. The most effective defoamers are long chain alcohols and commercially available silicone derivatives. Production aspects- 2. Chemical stability Chemical inertness is an absolute requirement for emulsion ingredients. Prediction of hydrolytic stability made by classic chemical or pharmaceutical procedures may be unreliable, as a result of micellar catalysis. This catalysis is observed when the reactive species are present on or near the micellar surface. Under these conditions hydrolytic (substitution) reactions can be accelerated. Hydrolysis of alkyl sulfates is an example of micellar catalysis. The hydrolysis of dodecyl sulfates depends on pH of the medium, and on variety of electrolytes and concentration of the surfactant. Production aspects- 3. Safety Safety and toxicologic clearance of components of pharmaceutical and cosmetic emulsions are absolute requirements. The formulator has enormous choice of emulsion ingredients, which differ in their cost and ability to yield the desired product. Stability of emulsions Thermodynamically emulsions are physically unstable. A reduction of the interfacial area by coalescence reduces the system’s energy and this process is thermodynamically favored. Garret defined a stable emulsion as “the one that would maintain the same number of sizes of particles of the dispersed phase per unit volume of weight of continuous phase. The total interfacial energy must be invariant with time to conform to this definition. A product’s shelf life may be directly related to its kinetic stability. Kinetic stability means that the physicochemical properties of an emulsion donot change appreciably during a reasonably long period of time. Thermodynamic stability is generally temperature dependent.  Symptoms of instability As soon as emulsion has been prepared, time and temperature dependent processes occur to effect its separation. An emulsion’s instability is evidenced by:- ❑ Creaming ❑ Reversible aggregation (flocculation) ❑ Irreversible aggregation (coalescence) ❑ Phase inversion Flocculation Flocculation is the reversible aggregation of droplets of the internal phase in the form of 3 dimensional clusters. It may take place before, during or after creaming. Flocculation is influenced by the charges on the surface of the emulsified globules. In the absence of a protective (mechanical) barrier at the interface, eg, insufficient emulsifier is present, emulsion droplets aggregate and coalesce rapidly. Flocculation can occur only when the mechanical or electrical barrier is sufficient to prevent droplet coalescence. In other words, flocculation differs from coalescence by the fact that the interfacial film and the individual droplets remain intact. The reversibility of this type of aggregation depends on the strength of interaction between particles, as determined by the nature of the emulsifier, phase volume ratio, the concentration of dissolved substances especially electrolytes and ionic emulsifiers. Flocculation Electrolytes are commonly used for demulsification, a modest level of electrolyte is helpful in stabilizing emulsions. Eg, Nacl reduces oil separation in a nujol/water emulsion exposed to ultracentrifugation. A high internal phase volume ie, tight packing of the dispersed phase tends to promote flocculation. Most practical o/w and w/o emulsions exists in a flocculated state. Flocculation, viscosity and shear thinning may be closely related. The viscosity of an emulsion depends to a large extent on flocculation, which restricts the movement of particles and can produce a fairly rigid network. Agitation of an emulsion breaks the particle-particle interaction with a resulting drop of viscosity. Creaming Under the influence of gravity, suspended particles or droplets tend to rise or sediment depending upon the differences in specific gravities between the phases. If creaming takes place without any aggregation, the emulsion can be reconstituted by shaking or mixing. Creaming involves the movement of a number of heterodisperse droplets, and their movements interfere with each other and may cause droplet deformation. If flocculation takes place, the criterion of sphericity is lost, and complex corrections for these variations must be made before stokes law can be applied quantitatively to the behavior of emulsions. Strokes equation is qualitatively applicable to emulsions. It shows that the rate of creaming is a function of the square of diameter of the droplet. Thus larger particles cream more rapidly than smaller particles. Formation of larger aggregates by coalescence and/ or by flocculation will accelerate creaming. The reverse is also true, ie, the smaller the particle size, less likely it is to cream. No creaming is possible if the specific gravities of the two phases are equal. Adjusting the specific gravity of the dispersed phase is a means of achieving improved emulsion stability. Rate of creaming is inversely proportional to the viscosity. Increased viscosity of the external phase is associated with improved shelf life. Creaming Coalescence It is the growth process during which the emulsified particles join to form larger particles which will eventually lead to separate completely or break. Mechanical strength of the interfacial tension is the major factor which prevents coalescence in emulsions. Thus it is recognized that good shelf life and absence of coalescence can be achieved by the formation of a thick interfacial film from macromolecules or from particulate solids. This is why a variety of natural gums and proteins are useful as auxiliary emulsifiers when used at low levels, but can be used as primary emulsifiers at higher concentrations.  Phase inversion “Change of emulsion type from o/w to w/o and vice versa.” Phase inversion can be brought about by: i. By adding electrolytes ii. By changing phase volume ratio i. By adding electrolytes If sufficient amount of electrolyte is added, salting out can occur, which may invert emulsion from o/w to w/o. e.g. when CaCl2 is added to o/w emulsion containing Na-stearate as emulgent, it can invert the emulsion from o/w to w/o due to formation of Ca-stearate  IV) Phase inversion ii. By changing phase volume ratio ✔ Phase volume ratio is the relative volume of the internal and external phase. ✔ The concentration of the internal phase above which the emulsifier can not produce a stable emulsion of desired type is called Critical point. ✔ Generally, a phase volume ratio of 50/50 results in most stable emulsion. ✔ However, a general emulsion may be prepared without inversion with as much as 74% of volume of the internal phase. PHASE INVERSION- BY CHANGING PHASE VOLUME RATIO Assessment of emulsion Shelf life The final acceptance of an emulsion depends on stability, appearance and functionality of the packaged product. No quick and sensitive methods for determining potential instability in an emulsion are available to the formulator. To speedup the stability program, the formulator commonly places the emulsion under some sort of stress. This method may eliminate many good emulsions because excessive artificial stress has been applied. An accelerated aging test should speed up only the processes involved in instability under “normal” storage conditions. If the stress is excessive, abnormal processes may come into play.  Assessment of emulsion ❑ Shelf life (stability) ❑ Parameters for evaluation of emulsion Stress conditions stability (shelf life) o Aging and temperature o Chemical parameters o Centrifugation o Agitation o Physical parameters ▪ phase separation ▪ Viscosity ▪ Electrophoretic properties - Zeta potential - Electrical conductivity ▪ Particle size number analysis  Stress conditions Stress conditions are normally employed for evaluating the stability of emulsion include:- I. Aging and temperature II. Centrifugation III. Agitation l. Aging and temperature The means of evaluating shelf life is cycling between two temperatures. Cycling should be conducted between 4 and 45 °C. This type of cycling approaches realistic shelf conditions, but places the emulsion under enough stress to alter various emulsion parameters. The normal effect of aging on emulsion at elevated temperature is acceleration of the rate of coalescence or creaming, and this is usually coupled with changes in viscosity. Most emulsions become thinner at elevated temperature and thicken when allowed to come to room temperature. This thickening can be excessive if the emulsion is not agitated during the cooling cycle. Sometimes, the low viscosity can be frozen into the emulsion if it is chilled rapidly. Freezing can damage an emulsion more than heating, since the solubility of emulsifiers is more sensitive to freezing than to modest warming. In addition, the formation of crystals develops pressure that can deform the spherical shape of emulsion droplets.  ll. Centrifugation Shelf life under normal storage conditions can be predicted rapidly by observing the separation of the dispersed phase due to either creaming or coalescence when the emulsion is exposed to centrifugation. According to stoke’s law creaming is a function of gravity, increasing which would accelerate separation. Becher indicates that centrifugation at 3750 rpm in a 10 cm radius centrifuge for a period of 5 hour is equivalent to the effect of gravity for about one year. Ultracentrifugation at extremely high speeds (approx. 25000 rpm or more) can be expected to cause effects that are not observed during normal aging of an emulsion. Ultracentrifugation of emulsions creates 3 layers:- A top layer or coagulated oil An intermediate layer of uncoagulated emulsion Essentially pure aqueous layer. Ultracentrifugation does not cause oil separation until it is high enough to break or rupture the absorbed layer of emulsifier that surrounds each droplet. Centrifugation is an extremely useful tool for evaluating and predicting the shelf life of emulsions. lll. Agitation No coalescence can take place unless droplets impinge upon each other owing to their Brownian movements. Simple mechanical agitation can contribute to the energy with which the droplets impinge upon each other. Excessive shaking of an emulsion or excessive homogenization has shown to interfere with the formation of an emulsion. Agitation can also break the emulsion. Some clear microemulsions can become cloudy upon short agitation in a blender due to coalescence of particles.  Parameters for evaluation of emulsion stability (shelf life) o Chemical parameters o Physical parameters ▪ Phase separation ▪ Viscosity ▪ Electrophoretic properties - Zeta potential - Electrical conductivity ▪ Particle size number analysis Chemical parameters The need for the chemical stability has already been established. A problem encountered in the presence of PEG or derivatives of PEG is their propensity towards auto-oxidation. This phenomena can cause formation of undesirable odors of acidic components and of all types of oxidative byproducts. The instability of non ionic esters to hydrolytic degradation may result in changes in the dielectric constant of the emulsion. Physical parameters The most commonly useful parameters commonly measured to assess the effect of stress conditions on emulsions include:- i. Phase separation ii. Viscosity iii. Electrophoretic properties iv. Particle size analysis and particle count i) Phase separation The rate and extent of phase separation may be observed visually or by measuring the volume of the separated phases. The means of determining phase separation involves withdrawing small specimens of the emulsion from top and bottom of the preparation after some period of storage and comparing the composition of the two samples by appropriate analysis of water content, oil content or any suitable constituent. ii) Viscosity As emulsions are generally non Newtonian and the instrument must have universal utility, it is best to avoid capillary and falling sphere viscometers. Viscometer of the cone plate type are used. In case of fairly viscous materials, penetrometer is used. As a rule, globules in freshly prepared w/o emulsion flocculates quite rapidly. Consequently, the viscosity drops quickly and continues to drop for some time(5-15 days) and then remains relatively constant. While in o/w emulsion, globule flocculation causes an immediate increase in viscosity. After this time, the change in consistency with time follows a linear relationship when plotted on log-log scale. Absence of slope (no viscosity change) is ideal. Most systems exhibit modest increase of viscosity. Others exhibit more drastic and sudden non linear increase in viscosity after 2 or 3 months aging. As a rule , decrease in viscosity with age reflects an increase of particle size due to coalescence and is indicative of poor shelf life. ii) Viscosity For determining creaming or sedimentation, before it becomes visibly apparent, utilizes a helipath attachment of the Brookfield viscometer. As a result of emulsion separation, the descending rotating spindle meets varying resistance at different levels and registers fluctuations in viscosity. It is impossible to predict long term viscosity behaviour from the data collected during first few weeks of storage after an emulsion has been prepared. The best way of using viscosity determinations for the prediction of shelf life is to relate them to changes in particle size. Viscosity measurements should be carried out in undisturbed containers. Studies should be carried out to determine the time necessary for a disturbed emulsion to recover its original viscosity. The viscosity of emulsions at several different shear rates must be determined to obtain a clear picture of rheology. iii) Electrophoretic properties The zeta potential of an emulsion can be measured with the aid of the moving boundary method or more quickly and directly by observing the movement of particles under the influence of electric current. The Zeta potential is useful for assessing flocculation since electric charges on particles influence the rate of flocculation. The measurement of electrical conductivity is a powerful tool for evaluation of emulsion stability shortly after preparation. The electrical conductivity of o/w or w/o emulsion is determined with the aid of Pt electrodes (dia 0.4mm, distance of 4mm) to produce current of about 15 -50 uA. Measurements are made on emulsions stored for short period of time at room temperature 37 C. The conductivity depends upon the degree of dispersion O/w preparations with fine particles exhibit low resistance, if the resistance increases, it is a sign of oil droplet aggregation and instability. A fine emulsion of w/o product does not conduct current until droplet coagulation ie, instability occurs. iv) Particle size number analysis Particle size measurement can be done with methods like Microscopy. It gives average diameter value depending upon the number of particles of each size. Some electronic devices measure particle size based on particle volume. These include coulter counter. It also requires that the emulsion should be diluted, sometimes with a conducting electrolyte. Light scattering technique has also been used. The change of reflectance can be linked with the particle diameter. The change of reflectance at wavelength at which colored internal phase partially absorbs the incident light is inversely proportional to the power of diameter. Practical recommendations for shelf life predictions Little evidence suggests that instability under stress can be related to normal shelf life. Therefore a realistic stability program has to be established to assess the shelf life of emulsions. A test program for an “acceptable” emulsion (in temperate zone) might establish the following: The emulsion should be stable with no visible signs of separation for at least 60-90 days at 45 or 50 C 5-6 months at 37 C And 12-18 months at room temperature. Similarly there should be no visible signs of separation after one month’s storage at 4C and preferably after 2 or 3 freeze thaw cycles between -20 and +25 C. An emulsion should survive atleast 6 or 8 heating/cooling cycles between refrigerator temperature and 45C with storage at each temperature of no less than 48hr. A stable emulsion should show no serious deterioration by centrifugation at 2000 to 3000 rpm at room temperature.  Practical recommendations for shelf life predictions The emulsion should not be adversely affected by agitation for 24 -48hrs on a reciprocating shaker (approx. 60 cycles per minute at room temperature and at 45 C). During the testing periods, the samples stored at various conditions should be observed critically for separation, and for the following characteristics at reasonable times: ▪ Change in electrical conductivity ▪ Change in light reflection ▪ Change in viscosity ▪ Change in particle size ▪ Change in chemical composition A shelf life program for emulsions should include testing for microbiological contamination at appropriate interval. Theory of emulsification When oil and water are mixed and agitated, droplets of varying sizes are produces an tension exists at the interface because both the immiscible phases tend to have different attractive forces for a molecule at interface. The greater the immiscibility, the greater is the interfacial tension. The interfacial tension is defined at a liquid interface is defined as the work required to create 1 cm2 of the new interface. A fine dispersion of oil and water necessitates a large area of interfacial contact which requires work equal to the product of interfacial tension and area change. A high interfacial free energy favors a reduction of interfacial area, by causing droplets to assume a spherical shape (min surface area) and by causing them to coalesce with a decrease in number of droplets.  Droplet stabilization Dispersions can be formed and stabilized by lowering the interfacial tension and/or by preventing the coalescing of droplets. According to classic emulsion theory, emulsifying agents are capable of performing both objectives. The materials commonly used as emulsifying agents can be divided into 3 categories:- ▪ Surface active agents ▪ Hydrophilic colloids ▪ Finely divided solids They reduce interfacial tension, and act as barriers to droplet coalescence since they are adsorbed at the interface, or on the surface of droplets. Emulsifying agents form emulsions by 3 mechanisms:- 1. Reduction of interfacial tension – thermodynamic stabilization 2. Interfacial film formation – mechanical barrier to coalescence 3. Electrical repulsion- electrical barrier approach of particles 1. Reduction of interfacial tension The adsorption of a surfactant lowers the interfacial tension between two liquids and thus prevents coalescence or phase separation. The role of the emulsifying agent as interfacial barrier is most important. Many polymers and finely divided solids are not effective in reducing interfacial tension, from excellent interfacial barriers and act to prevent coalescence and hence used as emulsifying agents. 2. Interfacial film formation It is considered as extended interfacial tension theory, in which the adsorbed emulsifier at the interface surrounds the dispersed droplets forming a coherent monomolecular or multimolecular film, which prevents the coalescence, as the droplets approach each other. The stability of emulsions depends on the characteristics of the film formed at the interface which in turn depends upon the type of emulsifier. a) Surface active agents – monomolecular film formation An amphiphilic molecule align itself at a water-oil interface in the most energetically favorable position- oleophilic portion in the oil phase and hydrophilic portion in the aqueous phase. Surface active agents tend to concentrate at interfaces and are adsorbed at oil water interfaces as monomolecular films. These films depend upon the nature, characteristics and concentration and combination of surfactants. i) Gaseous films:- In such films, the adsorbed surfactant molecules separate, donot adhere to each other laterally and move freely around the interface. Eg is the film that is formed by anionic surfactant, sodium dodecyl sulfate. When the film is strongly anchored to the dispersed phase droplet, the emulsion is stable. If the monolayer is loosely fixed, the adsorbed molecules move away from the interface and coalescence occurs. a) Surface active agents – monomolecular film formation ii) Condensed films:- If the concentration of the emulsifier is high enough, it forms a rigid film between the immiscible phases, which acts as a barrier to both adhesion and coalescence. The molecules of the long straight chain fatty acids, such as palmitic and stearic acids are more tightly packed. The hydrocarbon chains are adjacent to and in cohesive contact to one another. As the chain interlock, the molecules do not freely move in the interface leading to a stable emulsion. a) Surface active agents – monomolecular film formation iii) Expanded films:- The films formed by oleic acid are more expanded films. The hydrocarbon chains in oleic acid are less cohesive and less orderly packed in a liquid. The unsaturated double bond is polar and has greater affinity for water. The presence of branches and bent shaped hydrocarbons, bulky head groups and multiple polar groups cause lateral cohesion to be reduced and expanded films to form. Non ionic surfactants produce interfacial films in such fashion. There is no charge repulsion contribution, however the polar polyoxyethylene groups of surfactants are hydrated and bulky, causing steric hindrance among droplets and preventing coalescence. a) Surface active agents – monomolecular film formation iv) Interfacial complex condensed films:- In stable emulsions, the molecules in surface active agents are closely packed and form a tough interfacial film. This film is flexible, highly viscous, coherent, elastic, and resistant to rupture since the molecules are efficiently packed. To improve the stability, the combinations of surfactants are often used. Combination of a water soluble surfactant that produces a gaseous film, and an oil soluble auxiliary surfactant produces a stable interfacial complex condensed film. Most emulsifiers form fairly dense structures at the interface and produce a stable interfacial film. a) Surface active agents – monomolecular film formation v) Lamellar liquid crystalline films: Stable emulsions comprise liquid crystalline layers on the interface of emulsified droplets with the continuous phase. Friberg and coworkers showed by optical (polarized light) and electron microscopy and low angle X ray diffractometry that mixed emulsifiers can interact with water to form 3 D association structures. The classic concept of emulsions as two phase systems with a monomolecular layer of emulsifier at the interface must be revised. Emulsions should instead be viewed as three component systems comprising oil, water and lamellar liquid crystals (consisting of consecutive layers of water emulsifier oil water). Interlamellar layers have been identified by freeze fracture micrography of o/w creams. b) Hydrophilic colloids – multimolecular film formation Hydrophilic colloids such as polysaccharides and proteins do not lower the interfacial tension appreciable but form a multimolecular film at the oil- water interface. These films are strong and elastic and give mechanical protection to coalescence. An additional effect of these colloids is the electrostatic charge repulsion due to the carboxylic acid groups of polysaccharides and amino acid groups of proteins. These are used to stabilize emulsions and form o/w type emulsions. c) Finely divided solids- solid particle film formation Finely divided solid particles, adhere strongly to each other forming a stable film at the surface. They form stable emulsions preferentially wetted by one of the phases. When wetted by water, the contact angle is less than 90, and o/w type emulsion is formed, while when wetted by oil, w/o type emulsions are formed. 3) Electrical repulsion The interfacial and lamellar liquid crystal films can produce repulsive electrical forces between approaching droplets. Such repulsion is due to an electrical double layer, which may arise from electrically charged groups oriented on the surface of emulsified globules. Let us consider a case of an o/w emulsions stabilized by a sodium soap. The surfactant molecules are concentrated in the interface and oriented as well. The hydrocarbon tail is dissolved in the oil droplet, while the ionic heads are facing the continuous aqueous phase. The droplet surface is studied with charged groups ie, negatively charged carboxylate groups. This produces a surface charge on the droplet, while cation of opposite sign are oriented near the surface producing diffused double layer of charge. The potential produced by the double layer creates a repulsive effect between the oil droplets and thus hinders the coalescence. 3) Electrical repulsion References Bentley, chapter 20 (Coarse dispersion), page 291- 307) Industrial pharmacy by Lachman/ Lieberman, 4 th edition, chapter 18, page 680-716 Aulton’s pharmaceutical (3rd edition), the design and manufacture of medicines. (page 92-98) THANK YOU!!